ABSTRACT This revision application entitled ?Regeneration of acutely injured lungs using adult human stem cells? is to expand the scope of the parent grant ?Modeling, pathogenesis and treatment of idiopathic pulmonary fibrosis? into studies that will further regenerative medicine and accelerate its use by developing an adult stem cell therapy for acute lung injury. The treatment modality we propose is to regenerate acutely injured lungs by targeted removal of damaged pulmonary epithelium (while preserving lung vasculature and surrounding parenchymal tissue), followed by delivery of iPSC-derived pulmonary cells. Both the parent grant and this application are based on three highly innovative translational technologies recently developed in our labs: (i) derivation of large numbers of pulmonary progenitors from adult human iPSCs, (ii) prolongation of ex vivo lung support from 6 hours to 3?5 days by normothermic cross-circulation, and (iii) a non- invasive theranostic system for real-time monitoring of cell delivery and lung regeneration. For maximal significance, we focus on one of the most common causes of acute lung injury - gastric aspiration - that frequently leads to acute respiratory distress syndrome (ARDS). For maximal translational potential, we chose to develop an in-situ approach to lung regeneration, where an interventional procedure will be performed in the patient, by replacing defective cells in the region(s) of injury with therapeutic human iPSC-derived pulmonary cells using a very thin, flexible, imaging-guided bronchoscope. We will study lung regeneration ex vivo under cross-circulation and ventilation (over 3?5 days) and in situ (over 1 month) in a clinically relevant porcine model, using protocols established in our previous and preliminary studies. The project is designed to collect data for preparing the IRB/FDA applications for Phase I human trials to treat acute lung injury with therapeutic human iPSC-derived pulmonary cells by the end of the 1-year grant.